Use of non-steroidal anti-inflammatory agents to improve the physiological compatibility of particulate pharmaceutical preparations

ABSTRACT

The use of nonsteroidal anti-inflammatory agents as an addition to particulate pharmaceutical agent preparations can reduce side-effects on the cardiovascular system during administration.

This is a 371 of PCT/EP96/01936 filed May 9, 1996.

SUBJECT OF THE INVENTION

The invention relates to the subjects that are characterized in theclaims, i.e., the use of nonsteroidal anti-inflammatory agents toimprove the physiological compatibility of particulate pharmaceuticalagent preparations.

PRIOR ART

Particulate pharmaceutical preparations, such as, e.g., liposomes,magnetites, cavisomes, nanoparticles, etc., have in recent years gainedincreasing importance in both diagnosis and therapy. Some of theseparticulate systems, especially liposomes and cavisomes, can in turn besuitable as vehicle systems for transporting diagnostically significantcompounds, such as, e.g., contrast media or therapeutically usablesubstances, such as, e.g., gentamicin (INN). (Seltzer, S.: Liposomes inDiagnostic Imaging, in: Gregoriadis, G. (ed.), Liposomes as DrugCarriers, J. Wiley & Sons, Ltd., Chichester, New York, Brisbane,Toronto, Singapore, 1988).

After intravenous administration, such particulate vehicle systems areconcentrated preferably in the organs of the mononuclear phagocytesystem (RES), whereby the highest concentrations were reached in theliver and spleen (Krause, W. et al., J. Liposome Research 1995; 5:1-26).

WO88/09165 describes injectable aqueous liposome preparations withiodine-containing x-ray contrast media, as well as a process for theproduction of corresponding formulations. Owing to the sizes (0.15-0.3μm), as well as the high contrast medium inclusions (iodine/lipidquotient 1.5-6), these formulations are especially suitable forvisualizing the liver.

Very high dosages, which may very well be in the order of magnitude of10 g of lipid and more, are necessary especially for the particulateformulations that are used in diagnosis, and here again mainly for thepreparations that are used in diagnostic radiology (standard x-ray, butalso computer tomography). The result is strong activation of thereticuloendothelial system (RES) and other defense mechanisms. This canresult in, i.a., the reactions described below: a drop in the mean andarterial blood pressure and peripheral resistance, and an increase inheart rate, contractility, cardiac output, and pressure in the pulmonarycirculation.

Waddel et al. (J. Lab. Clin. Med. 1955; 45:697-710) describe theseside-effects in patients after injection of lipid emulsions as follows:reddening of the skin, sensation of warmth in the face and on the neck,agitation, sensation of stenosis or pressure in the chest area,cyanosis, and strong back pains. The administration of antihistamines isnot able to eliminate or mitigate these side-effects.

Behan et al. (AJR 1993; 160:399-405) observed a similar side-effectspectrum after an emulsion of perfluorooctylbromide was infused.Although it was possible to alleviate these effects with hydrocortisone,this compound is not used for computer tomography because of the highrisk of side-effects. Similar results were described by Vercelloti etal. (Blood 1982; 59:1299-1304).

Rabinovici et al. (Circ. Shock 1990; 31:431-445) speculate that theundesirable effects of liposomes with encapsulated hemoglobin areattributable to the release of PAF (platelet-activating factor), andthey attempted--successfully--to inhibit them by administering a PAFantagonist.

After administration of diatrizoate-containing liposomes to patientswith Hodgkins lymphoma, cirrhosis of the liver, or liver tumors,Rosenberg et al. (Vestn. Rontgenol. Radiol. 5:35-8, 1993) describeside-effects such as elevated temperature and fever in 30% of thepatients. It was possible to reduce or eliminate these effects bypretreatment with prednisolone (INN) and pipolphen.

It has now been found, surprisingly enough, that a direct addition ofnonsteroidal anti-inflammatory agents to particulate formulations notonly can reduce the undesirable effects on the cardiovascular system,but can even completely prevent them.

This is especially surprising because the side-effects without additionof nonsteroidal anti-inflammatory agents begin immediately after thestart of the administration (see FIG. 1). The elimination ofside-effects by nonsteroidal anti-inflammatory agents is thereforeeffective even at the low starting concentration of these substances inthe blood stream that is present at the beginning of the administration.

DESCRIPTION OF THE SUBJECT OF THE INVENTION

The subject of this invention is the use of nonsteroidalanti-inflammatory agents to improve the physiological compatibility ofparticulate pharmaceutical preparations.

As particulate pharmaceutical preparations, magnetites, nanoparticles,cavisomes, or liposomes, especially liposomes, which contain x-ray orNMR contrast media, can be used. Particles that are used as vehicles fordiagnostic agents or therapeutic agents are also suitable, however. Thecorresponding preparation can always be administered at the dose that iscommonly used and that contains the commonly used galenic additives.

As nonsteroidal anti-inflammatory agents, for example, acetylsalicylicacid, indomethacin (INN), ibuprofen (INN) or ketoprofen (INN),especially acetylsalicylic acid, can be used. The anti-inflammatoryagents can be contained in the pharmaceutical agent at the commonly useddose, e.g.: acetylsalicylic acid at a dose of 0.1-50 mg/kg of bodyweight, preferably 5-15 mg/kg of body weight.

Such pharmaceutical preparations and agents are therefore also thesubject of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Is a graph of mean arterial blood pressure in rats versus time(N=6; mean value ±SEM) after injection of liposomes withoutacetylsalicylic acid (⋄), of liposomes with acetylsalicylic acid(.increment.) and of a mannitol solution with acetylsalicylic acid (x).

FIG. 2 Is a graph of plumonary arterial pressure (PAP) in German landrace pigs versus time (N=6; mean value±SEM) after injection of liposomes(10 mg of iodine/kg) without acetylsalicylic acid premedication (□) orwith acetylsalicylic acid premedication (♦).

FIG. 3 Is a graph of cardiac output of the right ventricle in Germanland race pigs verses time (N=6; mean value±SEM) after injection ofliposomes (10 mg. of iodine/Kg) without acetylsalicylic acidpremedication (□) or with acetylsalicylic acid premedication (♦).

FIG. 4: Is a graph of pulmonary arterial pressure PAP in German landrace pigs verses time (N=3; mean value±SEM) after injection of liposomes(250 mg of iodine/kg) with acetylsalicylic acid premedication (♦) incomparison with the control (Ultravist) (□).

The following examples are intended to explain the invention, withoutintending that they have a limiting effect.

EXAMPLE 1

Male Wistar rats (350 g, N=6) were anesthetized with pentobarbital-Na(60 mg/kg i.p.) and then received an intravenous injection of liposomesthat were charged with the x-ray contrast medium iopromide (INN). Theparticle diameter of the liposomes was about 0.5 μm, and the compositionconsisted of soy phosphatidylcholine/cholesterol/stearic acid (4:5:1,suspension in mannitol solution). The dose was 300 mg of iodine/kg, andthe rate of injection 100 mg of iodine/kg/minute. As a control, amannitol solution (300 mmol, identical volume) was examined in N=4animals. In another group of N=6 rats, acetylsalicylic acid solution(Aspisol®; 4 mg/ml) was added to the liposome suspension by mixing inthe syringe.

Unlike in the mannitol control, the administration of the liposomeformulation resulted in a strong reduction in mean blood pressure (to60% of the starting value). With the addition of acetylsalicylic acid,the hemodynamic side-effects that are normally to be observed from theliposomes were completely prevented.

The results are depicted in FIG. 1.

EXAMPLE 2

After premedication, male German land race pigs (40 kg, N=6) wereintubated with azaperone/ketamines (1.5/10 mg/kg) and supplied with airwith a mixture of nitrous oxide/oxygen (3:1) and 1% by volume ofenfluane. After muscle relaxation with 0.1 mg/kg of pancuronium bromide,the right jugular vein and the right carotid artery were cannulated. Atip manometer was pushed via the jugular vein through the right cardiacventricle into the pulmonary artery to measure pressure (PAP). Adouble-sensor tip manometer was implanted via the carotid artery tomeasure blood pressure (BP) and the pressure in the left cardiacventricle (LVP). The electrocardiogram (EKG), the heart rate (HR), andthe pressure increase or drop rate (dP/dtmax and min) were also recordedcontinuously. In addition, after medisternal thoracotomy, cardiac outputrelating to the right ventricle (SV) and cardiac output (CO) weremeasured.

Then, after a suitable adaptation period, the animals received aninfusion of liposomes that were charged with an x-ray contrast medium.The particle diameter was about 0.2 μm, and the composition consisted ofsoy phosphatidylcholine/cholesterol/soy phosphatidyl glycerol (6:3:1).The dose was 10 or 250 mg of iodine/kg, and the rate of injection was 10mg of iodine/kg/minute. In pigs the administration of the liposomeformulation (10 mg of iodine/kg) led to an increase in PAP and adecrease in CO.

By premedication with acetylsalicylic acid (ASA, 10 mg/kg), it waspossible to completely prevent these circulatory side-effects (FIG. 2and 3). By premedication with ASA (10 mg/kg) 5 minutes before theliposome infusion, it was also possible to completely prevent allside-effects at a liposome dose of 250 mg/kg (FIG. 4).

We claim:
 1. A method of using non-steroidal anti-inflammatory agents which comprises incorporating a non-steroidal anti-inflammatory agent into a particulate pharmaceutical preparation in an amount sufficient to improve the physiological compatibility of said particulate pharmaceutical preparation.
 2. A method as in claim 1 wherein the non-steroidal anti-inflammatory agent is selected from the group consisting of acetylsalicylic acid, indomethacin (INN), ibuprofen (INN), and ketoprofen (INN).
 3. A method of using non-steroidal anti-inflammatory agents which comprises adding a non-steroidal anti-inflammatory agent to magnetites, nanoparticles, cavisomes, liposomes, or particulate vehicle systems.
 4. A method of using non-steroidal anti-inflammatory agents which comprises adding a non-steroidal anti-inflammatory agent to liposomes that contain contrast media.
 5. A method of using non-steroidal anti-inflammatory agents which comprises adding a non-steroidal anti-inflammatory agent to particulate vehicle systems that contain diagnostic agents and/or therapeutic agents.
 6. Pharmaceutical preparation that contains at least one x-ray and/or NMR contrast medium in combination with at least one nonsteroidal anti-inflammatory agent.
 7. Pharmaceutical preparation according to claim 6 that contains at least one x-ray and/or NMR contrast medium that is encapsulated in liposomes in combination with at least one nonsteroidal anti-inflammatory agent.
 8. Pharmaceutical preparation according to claim 6 that contains acetylsalicylic acid.
 9. Pharmaceutical preparation according to claim 7 that contains acetylsalicylic acid. 